Pyridylethylated d-alpha-methylphenethylamines



p and said substituted phenyl is selected from consisting of loweralkoxylphenyl and 3,4,5-t-rimethoxy.

3,055,906 Patented Sept. 25, 1962 This invention is concerned withpyridylethylated d-u-methylphenethylamines and derivatives thereof whichare effective agents in modifying central nervous system activity. 'Inparticular, the invention is concerned with pyridylethylatedd-wmethylphenethylamines of the structure shown vinylpyridine beingderived from the group consisting of 2- and 4-vinylpyridine and the ringalkylated derivatives of 2- and 4-vinylpyridines. The most eflicientprocedure has proven to be the acetic acid catalyzed condensation asdescribed by Reich and Levine, J. Am. Chem. Soc., 77: 5434 (1955).

After a suitable reaction period under reflux, the products arecollected by fractional distillation. The amines are secondary aminesand can be readily converted to their monoand dihydrochlorides andsimilar acid salts.

In turn, the secondary amine is readily acylated or aroylated upontreatment with acid chlorides of the type RCOCI wherein R has thesignificance described above.

The acylated and aroylated derivatives upon treatment with mineral acidsgive the corresponding acid salts and upon treatment with lower alkylhalides or sulfates afford the corresponding quaternary ammonium salts.

Typical compounds representing the structural ambit of this inventionare described in the table below:

TABLE Analyses Yield, N o. R M.P. n or per- Formula Carbon, per-Hydrogen, per- Nitrogen, per- B.P., 0 cent cent cent cent Calcd. FoundCalcd Found Calcd. Found 120 (0.05) E 66 C1eH2oN'2 80. 0 80. 1 8. 4 8. 211.7 12.0 170-179 (0.16) 87 ClsH22N.0 9. 9 10. 1 151-152 85CreHzsINzO--. 53. 8 54. 0 5. 9 6. 0 6. 6 6. 8 p-OH3OCeH C O 238-242(0.03)-- 39 Cz4H2uN202 77.0 77.0 7 0 6. 7 7. 5 7.0 o-C2H OOaH4CO..226-229 (0.03).- 47 OH28N202--- 7. 2 6. 8 Il\ IB 117-118 58 CzcHaoNzO-i.71. 9 71.7 7.0 7. 2 6. 5 6.0 128-134 (0.08) E 53 CrsHzuNz 80.0 79. 5 8.4 8. 4 11. 7 11. 7 103-106 Ob 57 Cz5HzaN2Oz 77.3 77.4 7. 3 7.1 7.2 6.9148-150 (0.4) E 01s 24N2 80. 6 80. 7 9. 0 9. 1 l0. 4 9. 8

B Py=2-pyridyl unless otherwise indicated; b Melting points are notcorrected and were 1w Py=4-pyridyl; Py=6-ethyl-2-pyridyl. established ona Fisher-Johns melting point block.

Recrystallizing solvent; M ethyl acetate; vb hexane-benzene. d Yieldsare expressed as recrystallized or distilled product.

8 Analyses are 1 Compound is s [111 in methanol; compound 11TMB=3,4,5-tri.methoxybenzo methiodide of compound 2.

l @om-on-g-nm-om-m wherein R is lower alkyl, phenyl and substitutedphenyl the group and 4-pyridyl e compounds of this invention on testingshow diverse yet unambiguous response in their effect on the centralnervous system in that they either promote central nervous systemactivity or significantly depress such activity.

While the exact mechanism of the pharmacological response to thecompounds of this invention is as yet unknown, it would appear that theyact and mediate central nervous system responses which, depending on thestructure of the compound involved, are observable as a depressant oranaleptic pharmacological response.

The pyridylethylated d-a-methylphenethylamines of this invention areconveniently prepared by condensation of d-a-methylphenethylamine with avinylpyridine, said by Weller and Strauss, Oxford, England.

1, +21.40; compound 7, +2430; compound 9, +2230.

The invention will be further illustrated by description in connectionwith the following specific examples showing the preparation ofcompounds of the invention.

Example I N-d-a-methylphenethyl 2-(5 ethyl 2 pyridyl)ethylamine(Compound 9). A mixture of one-third mole each ofd-a-methylphenethylamine, Z-Vinyl 5 ethylpyridine, and acetic acid inml. of methanol was heated under reflux for 8 hours and distilled. Afterremoval of low boiling fractions, a forerun was collected at l28-l40(0.3 mm), and the product (41.5 g.) was obtained, B.P. 148-l50 (0.4mm.). The forerun, upon trituration with hexane, gave 2.4 g. (4.1% M.P.l26127, not depressing the melting point of authenticd-a-methylphenethylacetamide.

Compounds 1 and 7 were similarly prepared.

Example I] Acetamide of Compound 1 (Compound 2) .A mixture of 9.6 g.(0.04 mole) of Compound 1 and 10 ml. of acetic anhydride was heatedunder reflux for 1 hour. When cool, after addition of ml. of water, andbasification, the formed oil was extracted with 100 ml. of benzene andthe product was obtained by distillation, 9.77 g. (87%), B.P. 179 (0.16mm).

A solution of 2.8 g. (0.01 mole) of the compound in 25 ml. ofacetonitrile and 2 ml. of methyl iodide was refluxed for 2 hours, andupon cooling, yielded 3.6 g. (85%) of the methiodide (Compound 3).Attempted hydrogenation with rhodium on carbon afforded only unconvertedreactant.

Example 111 3,4,5-trimethoxybenzamide of Compound 1 (Compound 6) .-Asolution of 9.6 g. (0.04 mole) of compound 1 in 35 ml. of benzene wasadded dropwise under stirring over 1 hour to a solution of 4.6 g. (0.02mole) of 3,4,5- trimethoxybenzoyl chloride in 65 ml. of benzene whilemaintaining the temperature at 25-30". When addition was complete, thereaction mixture was heated under reflux for 1 hour and then stored at20 for 24 hours. After extraction with dilute hydrochloric acid, andbasification, 8.6 g. (98%) of product was separated and recrystallized.

It is to be noted that it is intended to cover all changes andmodifications of the examples of the invention herein chosen for thepurpose of illustration which do not constitute departures from thespirit and scope of the invention.

We claim:

1. The amide of the structure wherein Py is selected from the groupconsisting of 2- .pyridyl, 4-pyridyl, and 2-pyridyl-5-ethyl and R isselected from the group consisting of lower alkyl, phenyl, loweralkoxyphenyl, and 3,4,5-trimethoxyphenyl.

2. The compound of the formula 4. The compound of the formula N@om-thn-nuom-cmonto -00H3 I OCH! References Cited in the file of thispatent UNITED STATES PATENTS 2,792,403 Blicke May 14, 1957 2,843,594Leditschke et al. July 15, 1958 2,870,156 Perron et al. Jan. 20, 1959OTHER REFERENCES Noller: The Chemistry of Organic Compounds, 2nd

Ed., page 244 (Saunders) (1957).

1. THE AMIDE OF THE STRUCTURE